Aspirin for secondary cardiovascular disease prevention is well established, but treatment discontinuation, often because of gastrointestinal mucosal injury or symptoms, can lead to increased risk for cardiovascular events. Proton pump inhibitor therapy is recommended for aspirin-treated patients at gastrointestinal risk. PA32540 [enteric-coated aspirin (EC-ASA) 325 mg + immediate-release omeprazole 40 mg] was compared with EC-ASA 325 mg alone once daily for 6 months in 2 duplicate, randomized double-blind trials in gastrointestinal-risk patients taking aspirin for ≥3 months for secondary prevention. In this post hoc analysis, we determined the prevalence of endoscopic upper gastrointestinal ulcers at screening and whether baseline endoscopic gastric erosions impacted subsequent ulcer development. At the screening endoscopy, 6% of subjects had upper gastrointestinal ulcers (not eligible for randomization) and 40% had gastric erosions. Conditional logistic regression modeling showed that baseline gastric erosions are significantly associated with endoscopic gastric ulcer development (OR = 2.12, 95% confidence interval, 1.26-3.57). In subjects with baseline gastric erosion, 4.2% of PA32540-treated versus 13.0% of EC-ASA-treated subjects (P = 0.001) subsequently developed endoscopic gastric ulcers. These data suggest that gastric injury predisposes to gastric ulcer development when taking EC-ASA, and exposure to immediate-release omeprazole in the presence of aspirin therapy significantly reduces the likelihood of progressing to gastric ulcers.